Fullenkamp Colleen A, Hall Sarah L, Jaber Omar I, Pakalniskis Brittany L, Savage Erica C, Savage Johanna M, Ofori-Amanfo Georgina K, Lambertz Allyn M, Ivins Stephanie D, Stipp Christopher S, Miller Benjamin J, Milhem Mohammed M, Tanas Munir R
Department of Pathology, University of Iowa, Iowa City, IA, USA.
Department of Biology, University of Iowa, Iowa City, IA, USA.
Oncotarget. 2016 May 24;7(21):30094-108. doi: 10.18632/oncotarget.8979.
TAZ (WWTR1) and YAP are transcriptional coactivators and oncoproteins inhibited by the Hippo pathway. Herein we evaluate 159 sarcomas representing the most prevalent sarcoma types by immunohistochemistry for expression and activation (nuclear localization) of TAZ and YAP. We show that 50% of sarcomas demonstrate activation of YAP while 66% of sarcomas demonstrate activated TAZ. Differential activation of TAZ and YAP are identified in various sarcoma types. At an RNA level, expression of WWTR1 or YAP1 predicts overall survival in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. Immunohistochemistry demonstrates that TAZ and YAP expression and activation are positively correlated with grade in the well-differentiated liposarcoma to dedifferentiated liposarcoma tumor progression sequence as well as conventional chondrosarcomas. TAZ and YAP are constitutively activated oncoproteins in sarcoma cell lines. Knock-down of TAZ and YAP demonstrate differential activity for the two proteins. Verteporfin decreases colony formation in soft agar as well as CTGF expression in sarcoma cell lines harboring activated TAZ and YAP.
TAZ（WWTR1）和YAP是转录共激活因子和癌蛋白，受Hippo信号通路抑制。在此，我们通过免疫组织化学评估了159例代表最常见肉瘤类型的肉瘤，以检测TAZ和YAP的表达及激活情况（核定位）。我们发现，50%的肉瘤显示YAP激活，而66%的肉瘤显示TAZ激活。在不同类型的肉瘤中发现了TAZ和YAP的差异激活。在RNA水平上，WWTR1或YAP1的表达可预测未分化多形性肉瘤和去分化脂肪肉瘤的总生存期。免疫组织化学表明，在高分化脂肪肉瘤至去分化脂肪肉瘤的肿瘤进展序列以及传统软骨肉瘤中，TAZ和YAP的表达及激活与分级呈正相关。TAZ和YAP在肉瘤细胞系中是组成性激活的癌蛋白。敲低TAZ和YAP显示这两种蛋白具有不同的活性。维替泊芬可减少软琼脂中的集落形成以及含有激活的TAZ和YAP的肉瘤细胞系中的CTGF表达。
